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Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets

Francesca Sacco1, Anett Seelig2, Sean J Humphrey3

  • 1Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany; Department of Biology, University of Rome Tor Vergata, 00100 Rome, Italy.

Cell Metabolism
|March 19, 2019
PubMed

Insights

Type 2 diabetes involves declining pancreatic beta cell function. Inhibiting GSK3 kinase in beta cells restored insulin secretion, offering a potential new drug target for diabetes.

Area of Science:

  • Biochemistry
  • Endocrinology
  • Metabolic Diseases

Background:

  • Pancreatic beta cell dysfunction is key in type 2 diabetes pathogenesis.
  • Protein phosphorylation is crucial for insulin secretion, but its network changes in diabetic islets are unclear.

Purpose of the Study:

  • To investigate changes in protein phosphorylation signaling networks in diabetic islets.
  • To identify potential therapeutic targets for type 2 diabetes.

Main Methods:

  • High-sensitivity mass spectrometry-based proteomics and phosphoproteomics were used on islets from obese diabetic mice and human islets.
  • Quantitative analysis of over 6,500 proteins and 13,000 phosphopeptides.
  • Integration with signaling networks and pharmacological inhibition of identified kinases.

Main Results:

  • Significant remodeling of kinase hubs and signaling pathways was observed in diabetic islets.
  • GSK3 kinase was implicated in regulating the beta cell transcription factor PDX1.
  • GSK3 inhibition in human islets restored glucose-stimulated insulin secretion, counteracting glucotoxicity.

Conclusions:

  • GSK3 kinase plays a conserved, glucotoxicity-dependent role in regulating beta cell insulin secretion.
  • Pharmacological inhibition of GSK3 shows promise for rescuing beta cell function in type 2 diabetes.
  • This study provides a valuable resource for understanding diabetes mechanisms and identifying drug targets.

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